Anti-rheumatic agents and their use

ABSTRACT

Anti-rheumatic agents contain vitamin E in combination with vasodilators and/or blood circulation-promoting agents. A method of treating rheumatic diseases is disclosed also.

This application is a continuation of Ser. No. 700,462, filed Feb. 11,1985, now U.S. Pat. No. 4,612,194.

BACKGROUND OF THE INVENTION

The present invention relates to a new use of vitamin E.

Vitamin E is known as an antioxidant and protective vitamin forphospholipids of the cell membrane. Vitamin E maintains the permeabilityand stability of the cell membrane; cf. Lucy, Annals N.Y. Academy ofScience 203, p. 4 (1972). It is further that vitamin E has amembrane-sealing effect; cf. F. Mittel and G. Bodechtel, MunchnerMedizinische Wochenschrift 110 (1968, 36: pp. 1988-1993. Vitamin E hasalso been found to provide a protective effect for the cell membrane inerythrocytes, the simplest cells of the human body. In both animal andhuman tests, it has been proven that anemia is a first signal of avitamin E deficiency. The hemolysis of the erythrocytes will normalizeupon administration of high doses of vitamin E; cf. William J. DarbeyVitamin Horm., 26 (50) pp. 685-704 (1968) and Phelps DL Pediatrics 63(6) pp. 933-935 (1979). From these literature references, it is apparentthat, after the oral administration of from 200 to 800 mg of vitamin Eover a period of from 1 to 4 days, the hemolysis of the erythrocytes issignificantly improved as compared to erythrocytes hemolysis in thosepatients suffering from vitamin E deficiency.

Vitamin E has further been used to treat sickle cell anemia over aperiod of from 6 to 35 weeks; cf. Natt C.L. Am. J. Clin. 33, pp. 968-971(1980); Natt C.L. Am. J. Clin. Nutr. 32, pp. 1359-1362 (1979); Gawlik G.M. Fed. Proc. 35 (3), p. 252 (1976); and Gorash L. Bieri J. G. et al.,Univ. Conn. Farmington, CT.

It has further been known that a daily dose of 750 mg of vitamin E overa period of from 3 to 6 months was successfully used to treatthalassemia patients, whereupon a normalization of the hemolysis of theerythrocytes was observed; cf. Kahane I. ISR. J. Med. 12 (1), pp. 11-15(1976).

Vitamin E has further been successfully applied to patients sufferingfrom an acute hepatitis or an alcoholic hepatitis who have a vitamin Edeficiency in serum; cf. Yoshiakawa T., Takemura S., Kato H. et al.,Japan. J. Gastrovent, 74/7, pp. 732-739 (1977). Moreover, vitamin E hasbeen used to treat patients suffering from iron deficiency anemia, inwhich treatment vitamin E caused an improvement or normalization of thelipid metabolism in the bone marrow to occur in the course of from 4 to8 weeks; cf. Takoshi Itaga, Central Clinical Laboratory NagasakiUniversity of Medicine, Japan.

It has now surprisingly been found that combinations comprising vitaminE and vasodilators and/or blood circulation promoters are suitable forthe treatment of rheumatic diseases. This new range of indications wasnot foreseeable from the state of the art and opens a new wide field ofapplications for vitamin E.

SUMMARY OF THE INVENTION

Thus, it is an object of the present invention to provide agentscontaining vitamin E for the treatment of rheumatic diseases. Theseagents may be formulations for external and internal applications.

It is another object of the present invention to provide anti-rheumaticagents that contain vitamin E in combination with blood circulationpromoters, more specifically those promoting blood circulation in theskin region, and/or other vasodilators.

The term "rheumatic diseases" is understood to denote the pain andrestrictions to motion. There is a variety of causes therefor such as,e.g. cephalgia, brachialgia, lumbago, cardialgia, nephralgia, myalgia,and also neuralgiae, pains in the regions of the peripheral nerves. Forpurposes of the present invention, "rheumatic diseases" is intended tohave the general meaning as given above, that is, a disease causing painand restrictions to motion.

DETAILED DESCRIPTION OF THE INVENTION

It has surprisingly been found that the action of vitamin E issignificantly increased in the presence of vasodilators and/or bloodcirculation-promoting agents, and thereby the duration of treatment isshortened. The symptoms of the diseases will be more rapidly reduced.However, the combination preparations containing vitamin E will have tobe administered for an extended period of time, that is, for about 6months or more.

Also unexpectedly, the penetration of vitamin E through the skin is alsoparticularly increased by the presence of agents promoting bloodcirculation such as heparin sodium, Extract. Hippocastani etc., wherebythe effect of vitamin E is significantly enhanced. When heparin sodiumis used, a high dose of from 30,000 to 150,000 I.U. is preferred.

It has been found that upon application of the active substances(vasodilators and/or blood circulation-promoting agents) in combinationwith a sufficient dose of vitamin E, the duration of the treatment canbe substantially shortened. The symptoms of the disease will be fasterreduced so that after some time the dosages to be applied can belowered.

These results were not foreseeable and enable a therapy wherein part ofthe active chemical is replaced by a substance of natural origin whichsubstance, moreover, is substantially present in every cell of the body.

Agents that will essentially increase the action of vitamin E and,hence, can be used in the present invention are agents promoting theblood circulation such as Extract. Hippocastani, β-hydroxyethylrutoside,Extract. Arnicae, nicotinic acid, nicotinic acid ester and derivativesthereof, xanthinol nicotinate, inositol nicotinate, and salicylic acidor the esters thereof, dihydroergotoxine methanesulfonate,dihydroergocornine methanesulphonate, dihydroergocristinemethanesulphonate and 8-hydroxyethylsalicylate. It has now been foundthat upon application of these agents in combination with a sufficientdose of vitamin E, the symptoms in many patients will be faster reducedand, after some months, the amounts of these blood circulation promoterscan be lowered.

In addition to the aforementioned vasodilators and blood circulationpromoters, other similar products such as cinnarizine, vincamine etc.may also be used.

Combinations according to the invention containing sufficient amounts ofvitamin E also improve the blood circulation in the extremities, of theeye periphery, of the inner ear and of the cerebrum. If, in addition,dimethylaminoethanol is added to the combinations according to theinvention, the blood circulation in the brain, the stimulation of thecentral nervous system, and the concentrating ability are enhanced. Theefficacy of vitamin E in cases of the respective indications isparticularly surprising and allows vitamin E to be used in further newfields of application.

In oral anti-rheumatic agents, above all, a sufficient dosage of vitaminE which should be at least 150 mg as this amount is crucial for theefficacy of vitamin E in combination with vasodilators and/or bloodcirculation-promoting agents. Lower dosages of vitamin E are useless,since large parts thereof are destroyed by the gastric acid and therebylose their activity; cf. Arthur Vogelsang, in Angiology 21, pp. 275-279(1970).

If, in the past, sometimes low amounts of vitamin E, viz. up to 40 mg,have been employed in combination preparations, these amounts withcertainty were ineffective due to the low doses. For the treatment ofrheumatic diseases, the dosage of vitamin E should be in the range offrom 150 to 600 mg. Preferably dosage forms containing from 150 to 500mg of vitamin E are used. Typical combination preparations contain 200to 400 mg of vitamin E. More specifically, in the combinationscontaining nicotinic acid there are required high vitamin E doses ofbetween 300 and 500 mg per dosage unit.

In the oral dosage form, there may be employed as the vitamin E theester of natural origin or of synthetic origin as well as the freetocopherol. In the anti-rheumatic ointment or gel or cream,respectively, only the free tocopherol, such as D,L-alphatocopherol isused.

The agents according to the invention contain the conventional carriersand excipients in addition to vitamin E and the other activeingredients. Since vitamin E is liquid at normal temperatures, softgelatin capsules particularly offer themselves as a suitable applicationform. The other active ingredients are incorporated in the vitamin Eand, if desired, in a low-viscosity neutral oil and a solutizer in a perse known manner. In this step suitable emulsifiers, e.g. Tween, may beemployed. More specifically, there may be used the standard recipes ofthe firm Scherer, Eberbach, West Germany. The application in the form ofdrops, e.g. as an alcoholic solution, of the combinations according tothe invention may also be suitable.

More particularly, successful results have been obtained in thetreatment of rheumatic diseases by applying suppositories containingvitamin E. However, in the various fields of use and applications, thesuitable additives for assisting in the treatment had to be selected.The conventional excipients and carriers can be employed for formulatingsuppositories. Nevertheless, suppositories containing high doses ofvitamin E alone can also be used for the treatment of rheumaticdiseases.

The combination with blood circulation promoting agents such as, e.g.,Extract. Hippocastani or β-hydroxyethyl rutoside or rutoside derivativescontaining several hydroxyethyl groups, respectively, can be used.Nicotinic acid or its esters or derivatives such as, e.g. nicotinic acidbenzylester or nicotinic acid β-hydroxyethylester etc., may bebeneficial and may enhance the effect caused by vitamin E and shortenthe process of healing. The advantage of using suppositories resides inthat vitamin E is not destroyed by the action of gastric acid. Theresorption is increased by the use of emulsifiers such as, e.g., oleicacid alkyl ester.

As the conventional bases for ointments or creams, there may be usedEucerin cum aqua, Ungentum Cordes or Ungentum emulsificans cans as wellas other water-insoluble ointment bases and mixtures thereof. Forexample, suitable ointment bases are wool wax, petrolatum DAB 8, highlyfluid paraffin, and mixtures thereof. They may also contain emulsifierssuch as cetylstearylalcohol.

Also suitable as bases for ointments are Unguentum alcoholum lanaeaquosum containing about 5 to 10% of Cetiol (oleyl oleate) and Unguentumlanette, 24 parts of cetylstearylalcohol, 16 parts of Cetiol DAB 8, and60 parts of Aqua conservata.

When such a combination is applied, the vitamin E will readily penetrateinto the skin. Of course, further vitamins such as those of the Bcomplex, e.g. B₁, B₂ and B₆, and compatible anodynes such as localanesthetics may be added. Local anesthetics are vasodilators. They maybe added to the ointments as a surface anesthetic such as Anaesthesin(Ethaforum) or Tetracain (Pantocain) or they may be incorporated intothe capsules such as Procain or Procain hydrochloride, respectively.

The present invention further describes antirheumatic agents forexternal applications such as, e.g., a cream, a gel, an ointment or alotion containing vitamin E.

Such an ointment contains the following components: 70 to 30% by weight,preferably 60 to 40% by weight, of water, 30 to 5% by weight, preferably25 to 7% by weight, of Cetiol (oleyl oleate), and 30 to 2% by weight,preferably 25 to 2% by weight, of cetylstearylalcohol or other aliphaticalcohols.

In the place of the cetylstearylalcohol, there may also be used,altogether or in part, other emulsifying alcohols, such as, e.g.,aliphatic alcohols or wool wax alcohols or diols, respectively,stearinol, monoglycerides esterified with aliphatic acids or similarsubstances. There may also be added, e.g., paraffin or petrolatum orother suitable materials in order to render the ointment spreadable.Cetiol (oleyl oleate) may also be completely or partially replaced byother emulsifiers such as Tween 20 or Tween 80 etc.. It has been foundthat a particularly preferred combination as a base for ointments orcreams containing vitamin E is as follows:

30 to 20% by weight of cetylstearylalcohol,

20 to 10% by weight of Cetiol (oleyl oleate),

60 to 40% by weight of water (aqua conservata).

This ointment containing vitamin E will be immediately absorbed into theskin.

It has been known that ointment bases containing water such as Ungentumemulsificans aquosum and Unguentum alcoholum lanae aquosum are suitablefor processing water-soluble active substances. However, it issurprising that ointment bases containing water to an amount ofapproximately more than 50% are very well suitable for processinglipophilic active substances such as vitamin E. As the skin-stimulantsor skin blood circulation-promoters there are to be mentioned, forexample, Ol. juniperi, Ol. pini pumilionis (dwarf pine oil), Ol.eucalypti, Ol. rosmarinae, Tinct. camphorae (or camphor, respectively).

As vegetable vasodilators there are to be mentioned, e.g., Extract.calendulae from the flower and Herba calendulae. It has been determinedthat these vasodilators or blood circulation-promoters, respectively,significantly increase the effect of vitamin E and/or shorten theduration of the treatment, respectively, and remove the pain at longsight. At long sight, also the use of vitamin E also causesstabilization to be achieved and the symptoms to be permanently removed,so that the probability of a relapse will be very low.

There may also be used further derivatives of the bloodcirculation-promoting agents or vasodilators, respectively, e.g.trimethylol rutoside.

It has also unexpectedly been found that the antirheumatic agentsaccording to the present invention are particularly beneficial if thesemedicaments additionally contain vitamin A. More specifically, theduration of the treatment will be shortened. Thus, the inventionincludes those anti-rheumatic medicaments that contain the vitamins Aand E and blood circulation-promoting agents.

Vitamins A and E very strongly tend to clog in an aqueous medium, moreparticularly so in the presence of other active substances. Thus, it mayhappen that the lipophilic valuable substances are not absorbed.

It has now been determined that surprisingly small amounts of about 1%of an emulsifier are sufficient to prevent clogging. The activesubstances are more readily dispersed or suspended, respectively, in theaqueous medium. This is advantageous in that the absorption by theintestine is facilitated. A higher amount of emulsifier is notnecessary, as in most cases 1 to 7% will suffice to prevent clogging.Emulsifiers may be used in amounts up to 10% or even more, but theselarger amounts have the drawback that side-effects may possibly occurwhen the medicament is taken over an extended period of time.

Conventional emulsifiers as used in medical preparations can beemployed, such as Tween 20, Cremophor®, aliphatic alcohols, partiallyesterified triglycerides etc. However, in the present invention Tween 80and Cetiol are preferred. It has been observed that, upon the additionof about 10% of emulsifier, the emulsification is not substantiallyimproved over that effected by the addition of 5% of emulsifier.

Lecithin in a concentration between 1 and 13% may also be used asemulsifier. This favors the resorption of the combination of vitamins Aand E and more specifically the resorption of vitamin A. Small amountsof lecithin will suffice to prevent clogging of the lipophilic vitaminsand to positively affect the optimal resorption. Although upon the useof large amounts of lecithin, up to 50%, a positive effect isdeterminable, it is recommended to add about 1% of a conventionalemulsifier such as Tween 80, as thereby, the miscibility of lecithinwith the two other vitamins is positively affected and clogging isprevented. With respect to the resorption properties, the use ofconventional emulsifiers such as, e.g. Tween 80, in an amount of about1% together with from 1 to 13% of lecithin is particularly beneficial.There may also be used Tween 20, Cetiol (oleyl oleate) and Cremophor®types As the lecithin preparation, soybean lecithin is preferred.

Vitamin E can be used in any of its alpha forms, as free tocopherol oras an ester thereof. The ester may be an acetate, succinate or any otheracceptable ester. Dosage forms such as tablets and dragees using vitaminE in the solid state may be prepared. It may also be administered in analcoholic solution. Vitamin E is preferred to be administered in a highquantity per dosage unit, if possible between 200 and 600 mg andpreferably between 300 and 500 mg.

Vitamin A can be employed as vitamin A palmitate, vitamin A acetate, afurther ester of vitamin A or as beta-carotene.

The amount of vitamin A in the dosage unit is to be selected so that themaximum daily dose will not exceed 50,000 I.U., i.e. when two dosageunits are to be administered per day, the dosage unit should contain amaximum of 25,000 I.U.

Further additives such as, e.g., vitamins of the B series or analgesicsetc. may be included For example, as the agents promoting bloodcirculation, there may be used the following substances or derivativesthereof: Inositol nicotinate, nicotinic acid, Cinnarizine, Bencyclanhydrogen fumarate, Vincamine, dihydroergotoxine methanesulphonate,Pentoxifylline, beta-pyridylcarbinol, Bamethan sulfate, Gingkoflavoglycosides, beta-hydroxyethylrutoside, and Extract. Hippocastani.

The agents promoting blood circulation may also be used in their retardforms (sustained release drugs).

Combinations according to the present invention containing sufficientamounts of vitamin E also improve the blood circulation in theextremities, the periphery of the eye, the inner ear, and the cerebrum.The activity of vitamins A and E in the cases of these indications isparticularly surprising and will open further new fields of applicationsfor these vitamins. Numerous blood circulation-promoting agents such ashydroxyrutosides also have anticoagulant properties.

In anti-rheumatic plasters, vitamin E is added in the form ofD-alpha-tocopherol or D,L-alpha-tocopherol in an amount of from 0.02 to4 g, and preferably from 0.1 to 3 g. The combination with vasodilatorssuch as Extract. Arnicae and with blood circulation promoters such asExtract. Hippocastani or Extract. Capsicae and with pain-alleviatingdrugs such as Extract. Belladonnae is preferred.

The present invention is further illustrated by the followingnon-limiting examples showing typical combinations of active substancesand dosages.

EXAMPLE 1

There can be prepared 100 g of an ointment containing

400 mg of allantoin;

400 mg of Dexapanthenol;

5,000 mg of D-alpha-tocopherol; and

30,000 I.U. of heparin sodium.

EXAMPLE 2

There can be prepared 100 g of an ointment containing

2.5 g of O-(β-hydroxyethyl) rutoside and

6.5 g of D-alpha-tocopherol or D,L-alpha-tocopherol.

EXAMPLE 3

There can be prepared 100 g of an ointment containing

400 mg of allantoin;

400 mg of Dexapanthenol;

8.8 g of D-alpha-tocopherol or D,L-alpha-tocopherol; and

30,000 I.U. of heparin sodium.

EXAMPLE 4

There can be prepared 100 g of an ointment containing

4.5 g of Extract. Hippocastani (containing about 800 mg of escin) and

5.0 g of D-alpha-tocopherol.

EXAMPLE 5

There can be prepared 100 g of a gel containing 50,000 I.U. of heparinsodium;

12 g of Arnica flower extract ((1:10), alcohol 60%);

25 g Tinct. Hippocastani e sem. (1:1, equals 0.65 g of escin); and

7.5 g of D-alpha-tocopherol.

EXAMPLE 6

There can be prepared 100 g of a gel containing

7.0 g of β-hydroxyethyl salicylate and

7.0 g of D-alpha-tocopherol.

EXAMPLE 7

A plaster (15 cm×25 cm in size) for rheumatic disease treatment can beprepared containing on one side thereof

70 mg of Extract. Arnicae;

70 mg of Extract. Capsici;

30 mg of Extract. Belladonnae; and

1500 mg of D-alpha-tocopherol concentrate.

EXAMPLE 8

There can be prepared 100 g of an ointment containing

10 g of benzocain (anesthesin);

8 g of D-alpha-tocopherol-concentrate; and

1 g of benzyl nicotinate.

EXAMPLE 9

There can be prepared 100 g of an ointment containing

3 g of 8-hydroxyethyl salicylate;

1 g of benzyl nicotinate; and

7 g of D-alpha-tocopherol.

EXAMPLE 10

There can be prepared 100 g of an ointment containing

8 g of D-alpha-tocopherol;

400 mg of allantoin;

400 mg of Dexapanthenol; and

150,000 I.U. of heparin sodium.

EXAMPLE 11

There can be prepared, capsules each containing

250 mg of nicotinic acid;

400 mg of D,L-alpha-tocopherol acetate; and

150 mg of soybean oil.

EXAMPLE 12

There can be prepared, capsules each containing

200 mg of β-hydroxyethyl rutoside;

300 mg of D,L-alpha-tocopherol acetate; and

180 mg of soybean oil.

EXAMPLE 13

There can be prepared, capsules each containing

150 mg of Extract. Hippocastani (containing 25 mg of escin);

300 mg of D,L-alpha-tocopherol acetate; and

150 mg of soybean oil.

EXAMPLE 14

There can be prepared, capsules each containing

300 mg of xantinol nicotinate;

400 mg of D-alpha-tocopherol; and

190 mg of soybean oil.

EXAMPLE 15

There can be prepared, capsules each containing

150 mg of Extract. Hippocastani (containing 25 mg of escin);

250 mg of vitamin E; and

150 mg of soybean oil.

EXAMPLE 16

There can be prepared, capsules each containing

5 mg of vitamin B₁ ;

5 mg of vitamin B₂ ;

5 mg of vitamin B₆ ;

200 mg of β-hydroxyethyl rutoside;

300 mg of vitamin E;

50 mg of nicotinic acid amide; and

200 mg of soybean oil.

EXAMPLE 17

There can be prepared, capsules each containing

100 mg of nicotinic acid;

100 mg of extract from horse-chestnuts (containing 16 mg of escin);

300 mg of D-alpha-tocopherol acetate; and

200 mg of soybean oil.

EXAMPLE 18

There can be prepared, capsules each containing

200 mg of inositol nicotinate;

300 mg of D-alpha-tocopherol concentrate; and

150 mg of soybean oil.

EXAMPLE 19

There can be prepared, capsules each containing

50 mg of procaine hydrochloride;

400 mg of D-alpha-tocopherol concentrate; and

150 mg of soybean oil.

EXAMPLE 20

There can be prepared, capsules each containing

50 mg of procaine hydrochloride;

400 mg of D,L-alpha-tocopherol acetate;

5 mg of vitamin B₁ ;

5 mg of vitamin B₂ ;

5 mg of vitamin B₆ ; and

150 mg of soybean oil or corn oil.

EXAMPLE 21

Drops can be prepared wherein 100 ml of 90% ethyl alcohol contain

40 g of D,L-alpha-tocopherol acetate and

4.5 g of Extract. Hippocastani (containing 750 mg of escin).

EXAMPLE 22

There can be prepared, capsules each containing

4.5 mg of dihydroergotoxine methanesulfonate and

400 mg of D,L-alpha-tocopherol acetate.

EXAMPLE 23

There can be prepared, capsules each containing

50 mg of procaine hydrochloride;

200 mg of nicotinic acid;

400 mg of vitamin E; and

150 mg of corn oil.

EXAMPLE 24

There can be prepared, capsules each containing

150 mg of bencyclane hydrogenfumarate;

400 mg of vitamin E as D,L-alpha-tocopherol acetate; and 150 mg ofsoybean oil.

EXAMPLE 25

Suppositories are prepared containing

450 mg of D-alpha-tocopherol concentrate;

30 mg of nicotinic acid benzyl ester;

100 mg of a dried, de-proteinated aqueous extract from Testis bovis;

70 mg of Extract. muirae pumae sicc.; and

2.0 g of Stadimol.

EXAMPLE 26

Suppositories are prepared containing

450 mg of D,L-alpha-tocopherol;

4 mg of Cetiol (oleic acid oleyl ester};

150 mg of zinc oxide; and

2.0 g of Stadimol.

EXAMPLE 27

Suppositories are prepared containing

400 mg of vitamin E;

200 mg of β-hydroxyethyl rutoside;

40 mg of Cetiol; and

and 2.0 g of Stadimol.

EXAMPLE 28

Suppositories are prepared containing

350 mg of vitamin E

250 mg of Extract. Hippocastani (containing about 80 mg of escin); and

2.0 g of Stadimol.

EXAMPLE 29

Suppositories were prepared in accordance with Example 27, however using

300 mg of vitamin E and

200 mg of Triethylol rutoside.

EXAMPLE 30

There can be prepared, capsules each containing

    ______________________________________                                        Pentoxifyllin       400     mg;                                               vitamin E           400     mg;                                               vitamin A acetate   15,000  I.U.; and                                         soybean oil         120     mg.                                               ______________________________________                                    

EXAMPLE 31

There can be prepared, capsules each containing

    ______________________________________                                        Naftidirofuryl hydrogenoxalate                                                                      100     mg;                                             vitamin E             500     mg;                                             vitamin A palmitate   30,000  I.U.; and                                       soybean oil           150     mg.                                             ______________________________________                                    

EXAMPLE 32

There can be prepared, capsules each containing

    ______________________________________                                        Cinnarizine            75      mg;                                            vitamin E              400     mg;                                            vitamin A palmitate    15,000  I.U.;                                          vitamins B.sub.1, B.sub.2, B.sub.6 (in equal amounts)                                                10      mg;                                            vitamin B.sub.12       5       μg; and                                     soybean oil            150     mg.                                            ______________________________________                                    

EXAMPLE 33

There can be prepared 100 ml of drops containing in ethyl

    ______________________________________                                        alcohol                                                                       Cinnarizine         7.5      g;                                               vitamin E           4.0      g; and                                           vitamin A palmitate 2,500,000                                                                              units.                                           ______________________________________                                    

EXAMPLE 34

There can be prepared, capsules each containing

    ______________________________________                                        xantinol nicotinate   500     mg;                                             vitamin E (D,L-alpha-tocopherol)                                                                    400     mg;                                             vitamin A palmitate   10,000  I.U.                                            Tween 80              20      mg; and                                         soybean oil           150     mg.                                             ______________________________________                                    

EXAMPLE 35

There can be prepared 100 ml of drops containing in ethyl

    ______________________________________                                        alcohol                                                                       dihydroergotoxine methanesulfonate                                                                 1.5 g    (comprising                                     0.5 g of dihydroergocristine methanesulfonate,                                0.5 g of dihydroergocornine methanesulfonate,                                 0.333 g of alpha-dihydroergocryptine methansulfonate and                      0.167 g of β-dihydroergocryptine methanesulfonate);                      vitamin E (D,L-alpha-tocopherol                                                                    3.5 g;   and                                             acetate)                                                                      vitamin A palmitate  2,500,000                                                                              units.                                          ______________________________________                                    

EXAMPLE 36

There can be prepared, capsules each containing

    ______________________________________                                        β-pyridyl carbinol tartrate                                                                   360     mg                                               (conforming to 150 mg of                                                      pyridylcarbinol);                                                             D-alpha-tocopherol acetate                                                                         400     mg;                                              vitamin A palmitate  12,000  I.U.; and                                        soybean oil          150     mg.                                              ______________________________________                                    

EXAMPLE 37

There can be prepared, capsules each containing

    ______________________________________                                        DL-alpha-tocopherol  400     mg;                                              β-hydroxyethyl rutoside                                                                       300     mg;                                              vitamin A palmitate  15,000  I.U.; and                                        soybean oil          150     mg.                                              ______________________________________                                    

EXAMPLE 38

There can be prepared, capsules each containing

    ______________________________________                                        Gingko flavoglycosides  3.0     mg;                                           vitamin E DL-alpha-tocopherol acetate                                                                 300     mg;                                           vitamin A palmitate     25,000  I.U.; and                                     soybean oil             100     mg.                                           ______________________________________                                    

EXAMPLE 39

There can be prepared, capsules each containing

    ______________________________________                                        nicotinic acid       300     mg;                                              vitamin E            400     mg;                                              vitamin A palmitate  15,000  I.U.;                                            Cetiol (oleylic acid ester)                                                                        20      mg; and                                          soybean oil          150     mg.                                              ______________________________________                                    

EXAMPLE 40

There can be prepared, capsules each containing

    ______________________________________                                        DL-alpha-tocopherol acetate                                                                        400     mg;                                              β-Hydroxyethylrutoside                                                                        300     mg;                                              vitamin A palmitate  25,000  I.U.; and                                        soybean oil          120     mg.                                              ______________________________________                                    

EXAMPLE 41

There can be prepared, capsules each containing

    ______________________________________                                        Pentoxifylline          400     mg;                                           vitamin E DL-alpha-tocopherol acetate                                                                 400     mg;                                           vitamin A palmitate     15,000  I.U.;                                         Tween 80                10      mg; and                                       soybean oil             150     mg.                                           ______________________________________                                    

EXAMPLE 42

There can be prepared, capsules each containing

    ______________________________________                                        Bamethane sulfate    25      mg;                                              DL-alpha-tocopherol acetate                                                                        250     mg;                                              vitamin A palmitate  10,000  I.U.; and                                        soybean oil          150     mg.                                              ______________________________________                                    

EXAMPLE 43

There can be prepared, capsules each containing

    ______________________________________                                        Vincamine               30      mg;                                           vitamin E DL-alpha-tocopherolacetate                                                                  400     mg;                                           vitamin A palmitate     30,000  I.U.; and                                     soybean oil             150     mg.                                           ______________________________________                                    

EXAMPLE 44

An ointment can be prepared containing

10 g of D-alpha-tocopherol;

50,000 I.U. of heparin sodium; and

100 g of an ointment base comprising

22 parts of cetylstearylalcohol;

18 parts of Cetiol; and

60 parts of water.

EXAMPLE 45

An ointment can be prepared containing

7 g of vitamin E (D-alpha-tocopherol);

1 g of nicotinic acid benzyl ester;

1 g of camphor; and

100 g of an ointment base comprising

17 parts of cetylstearylalcohol;

8 parts of white petrolatum;

15 parts of Cetiol; and

60 parts of water (aqua conservata).

EXAMPLE 46

An ointment can be prepared containing

7 g of vitamin E;

15 g of Tinct. calendualae; and

100 g of an ointment base comprising

13 parts of wool wax alcohol;

2 parts of cetylstearylalcohol;

20 parts of Cetiol

5 parts of paraffin; and

50 parts of water (aqua conservata).

EXAMPLE 47

An ointment can be prepared containing

8 g of vitamin E (DL-alpha-tocopherol);

1.5 g of rosemary oil;

1 g of Extract. Hippocastani (standardized to at least 8% of escin);

1 g juniper oil; and

100 g of the ointment base of Example 44.

EXAMPLE 48

A solution can be prepared comprising

10 g of vitamin E (D-alpha-tocopherol concentrate);

1 g of dwarf pine oil (ol. pini pumilionis);

1 g of eucalyptus oil;

1 g of juniper oil; and

100 g of isopropyl alcohol.

EXAMPLE 49

An ointment can be prepared containing

7 g of D-alpha-tocopherol concentrate;

2 g of Tinct. arnicae;

2 g of salicylic acid β-hydroxyethyl ester; and

100 g of the ointment base of Example 44.

EXAMPLE 50

A solution similar to that in Example 48 can be prepared containing

7.0 g of vitamin E;

1.0 g dwarf pine oil;

1.0 g Tinct. arnicae; and

100 g of isopropyl alcohol.

EXAMPLE 51

An ointment can be prepared containing

9.0 g of vitamin E;

20.0 g Tinct. calendulae; and

100 g of the ointment base of Example 44.

The following Examples 52 through 66 relate to combinations of vitaminsE and A with lecithin.

EXAMPLE 52

There can be prepared, capsules each containing

    ______________________________________                                        Pentoxifylline          400     mg;                                           vitamin E (D,L-alpha-tocopherol acetate)                                                              400     mg;                                           vitamin A acetate       25,000  I.U.;                                         soybean lecithin        200     mg;                                           soybean oil             120     mg; and                                       Tween 80                8       mg.                                           ______________________________________                                    

EXAMPLE 53

There can be prepared, capsules each containing

    ______________________________________                                        Naftidirofuryl hydrogenoxalate                                                                        100     mg;                                           vitamin E (D-alpha-tocopherol-concentrate)                                                            500     mg;                                           vitamin A palmitate     30,000  I.U.                                          soybean lecithin        25      mg; and                                       soybean oil             150     mg.                                           ______________________________________                                    

EXAMPLE 54

There can be prepared, capsules each containing

    ______________________________________                                        Cinnarizine            75      mg;                                            vitamin E (D-alpha-tocopherol acetate)                                                               400     mg;                                            vitamin A palmitate    25,000  I.U.;                                          vitamins B.sub., B.sub.2, B.sub.6 (in equal amounts)                                                 10      mg;                                            vitamin B.sub.12       5       μg;                                         soybean oil            100     mg; and                                        soybean lecithin       280     mg.                                            ______________________________________                                    

EXAMPLE 55

There can be prepared 100 ml of drops containing in ethyl alcohol

    ______________________________________                                        alcohol                                                                       Cinnarizine        7.5      g;                                                vitamin E          4.0      g;                                                vitamin A palmitate                                                                              2,500,000                                                                              I.U.; and                                         lecithin           2.5      g.                                                ______________________________________                                    

EXAMPLE 56

There can be prepared, capsules each containing

    ______________________________________                                        Xantinol nicotinate   500     mg;                                             vitamin E (DL-alpha-tocopherol)                                                                     400     mg;                                             vitamin A palmitate   25,000  I.U.;                                           Tween 80              20      mg;                                             soybean oil           150     mg; and                                         soybean lecithin      25      mg.                                             ______________________________________                                    

EXAMPLE 57

There can be prepared 100 ml of drops containing in ethyl alcohol

    ______________________________________                                        dihydroergotoxine methanesulfonate                                                                 1.6      g(comprising                                    0.5 g of dihydroergocristine methanesulfonate,                                0.5 g of dihydroergocornine methanesulfonate,                                 0.333 g of alpha-dihydroergocryptine methanesulfonate and                     0.167 g of β-dihydroergocryptine methanesulfonate);                      vitamin E (DL-alpha-tocopherol                                                                     3.5      g;                                              acetate)                                                                      vitamin A palmitate  1,500,000                                                                              I.U.; and                                       soybean lecithin     3.5      g.                                              ______________________________________                                    

EXAMPLE 58

There can be prepared, capsules each containing

    ______________________________________                                        β-pyridyl carbinol tartrate                                                                      360     mg                                            corresponding to 150 mg of pyridyl carbinol;                                  D-alpha-tocopherol acetate                                                                            400     mg;                                           vitamin A palmitate     10,000  I.U.;                                         soybean oil             100     mg;                                           soybean lecithin        150     mg; and                                       Tween 20                6       mg.                                           ______________________________________                                    

EXAMPLE 59

There can be prepared, capsules each containing

    ______________________________________                                        DL-alpha-tocopherol  400     mg;                                              β-hydroxyethyl rutoside                                                                       300     mg;                                              vitamin A palmitate  30,000  I.U.;                                            soybean oil          100     mg; and                                          soybean lecithin     250     mg.                                              ______________________________________                                    

EXAMPLE 60

There can be prepared, capsules each containing

    ______________________________________                                        Gingko flavoglycosides  3.0     mg                                            vitamin E (D,L-alpha-tocopherol acetate                                                               300     mg                                            vitamin A palmitate     25,000  I.U.;                                         soybean oil             100     mg; and                                       soybean lecithin        200     mg.                                           ______________________________________                                    

EXAMPLE 61

There can be prepared, capsules each containing

    ______________________________________                                        nicotinic acid       300     mg;                                              vitamin E            400     mg;                                              vitamin A palmitate  15,000  I.U.;                                            Cetiol (Oleic acid ester)                                                                          10      mg;                                              soybean oil          100     mg; and                                          soybean lecithin     20      mg.                                              ______________________________________                                    

EXAMPLE 62

There can be prepared, capsules each containing

    ______________________________________                                        D-alpha-tocopherol   200    mg;                                               lecithin             500    mg;                                               soybean oil          180    mg; and                                           Tween 80             10     mg.                                               ______________________________________                                    

EXAMPLE 63

There can be prepared, capsules in accordance with Example 62 butadditionally containing 15,000 I.U. vitamin A palmitate.

EXAMPLE 64

There can be prepared, capsules in accordance with Examples 62 and 63but containing D,L-alpha-tocopherol acetate instead ofD-alpha-tocopherol.

EXAMPLE 65

There can be prepared, capsules each containing

    ______________________________________                                        D-alpha-tocopherol   400    mg;                                               lecithin             400    mg;                                               soybean oil          200    mg; and                                           Tween 80             15     mg.                                               ______________________________________                                    

EXAMPLE 66

There can be prepared, capsules in accordance with Example 65 butadditionally containing 15,000 I.U. vitamin A palmitate or vitamin Aacetate or 9.5 mg β-carotene.

The products shown in Examples 52 through 66 can be used as agents forlowering the cholesterol level.

The following Examples 67 through 95 relate to the additional use ofdimethylaminoethanol in the combinations according to the presentinvention.

EXAMPLE 67

There can be prepared a formulation containing

20 mg of dimethylaminoethanol;

400 mg of D,L-alpha-tocopherol acetate;

12,000 I.U. of vitamin A palmitate (6.67 mg);

50 mg of soybean oil;

200 mg of soybean lecithin; and

200 mg of β-hydroxyethylrutoside.

EXAMPLE 68

There can be prepared a formulation containing

20 mg of dimethylaminoethanol;

400 mg of D,L-alpha-tocopherol acetate;

12,000 I.U. of vitamin A palmitate (6.67 mg);

100 mg of soybean oil;

300 mg of lecithin; and

75 mg of Cinnarizine.

EXAMPLE 69

There can be prepared a formulation containing

25 mg of dimethylaminoethanol orotate;

400 mg of D,L-alpha-tocopherol acetate;

15,000 I.U. of vitamin A palmitate (8.33 mg);

20 mg of soybean lecithin; and

400 mg nicotinic acid.

EXAMPLE 70

There can be prepared a formulation as in Example 67, but additionallycontaining 8 mg of Tween 80.

EXAMPLE 71

There can be prepared a formulation containing

25 mg of dimethylaminoethanol orotate;

500 mg of D-alpha-tocopherol concentrate;

22,000 I.U. of vitamin A palmitate (12.22 mg);

28 mg of soybean lecithin;

120 mg of soybean oil; and

3.0 mg of Ginkoflavoglucoside

EXAMPLE 72

There can be prepared a formulation as in Example 71, but additionallycontaining 8 mg of Tween 20.

EXAMPLE 73

There can be prepared a formulation containing

30 mg of dimethylaminoethanol orotate;

400 mg of D,L-alpha-tocopherol acetate;

300 mg of lecithin;

8 mg of Tween 80; and

30 mg of Vincamine.

EXAMPLE 74

There can be prepared a formulation containing

25 mg of dimethylaminoethanol orotate;

350 mg of D-alpha-tocopherol acetate;

15,000 I.U. of vitamin A palmitate;

5 mg of each of the vitamins B₁, B₂, B₆ ;

5 μg of vitamin B₁₂ ;

15 mg of nicotinic acid amide;

280 mg of lecithin; and

75 mg Cinnarizine.

EXAMPLE 75

There can be prepared a formulation as in Example 74, but additionallycontaining 5 mg of Tween 80.

EXAMPLE 76

There can be prepared a formulation containing

25 mg of dimethylaminoethanol orotate;

400 mg of D,L-alpha-tocopherol acetate;

15,000 I.U. of vitamin A palmitate (8.33 mg); and

300 mg of β-hydroxyethylrutoside.

EXAMPLE 77

There can be prepared a formulation as in Example 76, but additionallycontaining 8 mg of Tween 80.

EXAMPLE 78

There can be prepared a formulation containing

35 mg dimethylaminoethanol orotate;

500 mg of D-alpha-tocopherol concentrate;

22,000 I.U. of vitamin A palmitate (12.22 mg); and

400 mg of xantinol nicotinate.

EXAMPLE 79

There can be prepared a formulation as in Example 78, but additionallycontaining 4 mg of Tween 20.

EXAMPLE 80

There can be prepared a formulation containing

30 mg of dimethylaminoethanol orotate;

400 mg of D,L-alpha-tocopherol acetate; and

400 mg of Pentoxyfylline.

EXAMPLE 81

There can be prepared a formulation containing

35 mg of dimethylaminoethanol orotate;

350 mg of D-alpha-tocopherol acetate;

15,000 I.U. of vitamin A palmitate;

5 mg of each of the vitamins B₁, B₂ and B₆ ;

5 μg of vitamin B₁₂ ; and

100 mg of Bencyclane fumarate.

EXAMPLE 82

There can be prepared a formulation as in Example 81, but alsocontaining 3 mg of Tween 80.

EXAMPLE 83

There can be prepared a formulation containing

25 mg of dimethylaminoethanol orotate;

350 mg of D,L-alpha-tocopherol acetate;

17,000 I.U. (9.44 mg) of vitamin A palmitate;

70 mg of soybean oil; and

75 mg Cinnarizine.

EXAMPLE 84

There can be prepared a formulation containing

20 mg of dimethylaminoethanol;

200 mg of D,L-alpha-tocopherol acetate;

12,000 I.U. of vitamin A palmitate (6.67 mg);

50 mg of soybean oil; and

250 mg of soybean lecithin.

EXAMPLE 85

There can be prepared a formulation containing

35 mg of dimethylaminoethanol orotate;

400 mg of D,L-alpha-tocopherol acetate;

15,000 I.U. of vitamin A palmitate (8.33 mg); and

20 mg of soybean lecithin.

EXAMPLE 86

There can be prepared a formulation as in Example 84, but additionallycontaining 3 mg of Tween 80.

EXAMPLE 87

There can be prepared a formulation containing

20 mg of dimethylaminoethanol;

200 mg of D,L-alpha-tocopherol acetate;

12,000 I.U. of vitamin A palmitate (6.67 mg); and

50 mg of soybean oil.

EXAMPLE 88

There can be prepared a formulation containing

35 mg of dimethylaminoethanol orotate;

400 mg of D,L-alpha-tocopherol acetate; and

15,000 I.U. of vitamin A palmitate (8.33 mg).

EXAMPLE 89

There can be prepared a formulation as in Example 87, but additionallycontaining 3 mg of Tween 80.

EXAMPLE 90

There can be prepared a formulation containing

35 mg of dimethylaminoethanol orotate;

500 mg of D-alpha-tocopherol concentrate; and

22,000 I.U. of vitamin A palmitate (12.22 mg).

EXAMPLE 91

There can be prepared a formulation as in Example 90, but additionallycontaining 4 mg of Tween 20.

EXAMPLE 92

There can be prepared a formulation containing

30 mg of dimethylaminoethanol orotate; and

400 mg of D,L-alpha-tocopherol acetate.

EXAMPLE 93

There can be prepared a formulation containing

35 mg of dimethylaminoethanol orotate;

350 mg of D-alpha-tocopherol acetate;

15,000 I.U. of vitamin A palmitate;

5 mg of each of the vitamins B₁, B₂ and B₆ ;

5 μg of vitamin B₁₂ ; and

15 mg of nicotinic acid amide.

EXAMPLE 94

There can be prepared a formulation as in Example 93, but additionallycontaining 3 mg of Tween 80.

EXAMPLE 95

There can be prepared a formulation containing

25 mg of dimethylaminoethanol orotate;

350 mg of D,L-alpha-tocopherol acetate;

17,000 I.U. (9.44 mg) of vitamin A palmitate; and

70 mg of soybean oil.

In the Examples soybean oil was used, when present, in an amount of from50 to 200 mg per capsule. However, other neutral oils such as olive oil,rape seed oil etc. can be used as well.

What is claimed is:
 1. A method for enhancing blood circulation in apatient in need thereof comprising administering to said patient vitaminE in an amount therapeutically effective to enhance said bloodcirculation wherein vitamin E is administered in combination with atherapeutically effective amount of a vasodilator and/or a bloodcirculation-promoting agent selected from the group consisting ofBencyclan hydrogenfumarate, dihydroergotoxine methanesulfonate,Pentoxifylline, gingko flavoglycosides, Extract. Hippocastani, andfunctionally effective derivatives thereof.
 2. The method of claim 1,wherein vitamin E is administered in the form of a plaster containingD-alpha-tocopherol or D,L-alpha-tocopherol, together with said bloodcirculation-promoting agent and/or vasodilator.
 3. The method of claim 1wherein vitamin E is administered along with said bloodcirculation-promoting agent and a therapeutically effective amount ofvitamin A.
 4. The method of claim 3, wherein vitamin E is administeredin an amount of from 200 to 600 mg per unit dosage form.
 5. The methodof claim 4, wherein vitamin E is administered in an amount of from 300to 500 mg per unit dosage form.
 6. The method of claim 3, wherein saidblood circulation-promoting agent is selected from the group consistingof Pentoxifylline or functionally effective derivatives thereof.
 7. Amethod for enhancing blood circulation in the extremities, eyeperiphery, inner ear and cerebrum in a patient in need thereofcomprising administering to said patient a therapeutically effectiveamount of at least one of the class of circulation enhancing agentsconsisting of Bencyclan hydrogenfumarate, dihydroergotoxinemethanesulfonate, Pentoxifylline, gingko flavoglycosides, Extract.Hippocastani, and functionally effective derivatives thereof as acirculation enhancing agent, and a therapeutically effective amount ofvitamin E effective for enhancing the blood circulating enhancing effectof said agent.
 8. The method of claim 7 wherein said combination isadministered topically.
 9. The method of claim 7 wherein saidcombination is administered orally.
 10. A blood circulation enhancingpharmaceutical comprising a therapeutically effective amount ofPentoxifylline, including functionally effective derivatives thereof asa circulation enhancing agent; and,a therapeutically effective amount ofvitamin E effective for enhancing the blood circulating enhancing effectof said agent.
 11. A blood circulation enhancing pharmaceuticalcomposition in dosage form comprising a therapeutically effective amountof Pentoxifylline, including functionally effective derivatives thereofas a circulation enhancing agent; and,a therapeutically effective amountof vitamin E effective for enhancing the blood circulating enhancingeffect of said agent.
 12. The composition of claim 11 in unit dosageform.
 13. The composition of claim 12 in capsule unit dosage form. 14.The composition of claim 11 in ointment form.
 15. A blood circulationenhancing pharmaceutical composition comprising a therapeuticallyeffective amount of vitamin E in combination with a therapeuticallyeffective amount of a vasodilator or a blood circulation-promoting agentselected from the group consisting of Bencyclan hydrogenfumarate,dihydroergotoxine methanesulfonate, Pentoxifylline, gingkoflavoglycosides, Extract. Hippocastani, and functionally effectivederivatives thereof.
 16. The composition of claim 15, wherein thecomposition is in capsule form.
 17. The composition of claim 15, whereinthe composition is in ointment form.
 18. The composition of claim 15,further comprising a therapeutically effective amount of vitamin A. 19.The composition of claim 15, further comprising an emulsifier.
 20. Thecomposition of claim 15, wherein vitamin E is present in an amount offrom 200 to 600 mg.